Local and long-distance inputs dynamically regulate striatal acetylcholine during decision making

Abstract

Within the basal ganglia, striatal dopamine (DA) and acetylcholine (Ach) are essential for the selection and reinforcement of motor actions and decision making. In vitro studies have revealed a circuit local to the striatum by which each of these two neurotransmitters directly regulates release of the other. Ach, released by a unique population of cholinergic interneurons (CINs), drives DA release via direct axonal depolarization. In turn, DA inhibits CIN activity via dopamine D2 receptors (D2R). Whether and how this circuit contributes to striatal function in vivo remains unknown. To define the in vivo role of this circuit, we monitored Ach and DA signals in the ventrolateral striatum of mice performing a reward-based decision-making task. We establish that DA and Ach exhibit multiphasic and anticorrelated transients that are modulated by decision history and reward outcome. However, CIN perturbations reveal that DA dynamics and reward-prediction error encoding do not require Ach release by CINs. On the other hand, CIN-specific deletion of D2Rs shows that DA inhibits Ach levels in a D2R-dependent manner, and loss of this regulation impairs decision-making. To determine how other inputs to striatum shape Ach signals, we assessed the contribution of projections from cortex and thalamus and found that glutamate release from both sources is required for Ach release. Altogether, we uncover a dynamic relationship between DA and Ach during decision making and reveal modes of CIN regulation by local DA signals and long-range cortical and thalamic inputs. These findings deepen our understanding of the neurochemical basis of decision making and behavior.

Striatal cholinergic interneuron pause response requires Kv1 channels, is absent in dyskinetic mice, and is restored by dopamine D5 receptor inverse agonism

“…Several studies support that dopamine positively modulates the pause response of SCIN through D2Rmediated effects (Watanabe and Kimura, 1998;Ding et al, 2010;Kharkwal et al, 2016) and constitutive ablation of D2R from cholinergic neurons disrupts the anticorrelated DA-ACh signal during specific portions of an operant task (Chantranupong et al, 2023). However, striatal ACh transients persist and even increase after the blockade of striatal DA receptors or lesion of nigrostriatal neurons, while they are reduced after intrastriatal infusion of glutamate receptor antagonists (Krok et al, 2023).…”

“…Recent in vivo studies showed anticorrelated changes of DA and ACh striatal levels, not only during rewarded tasks but also during spontaneous behavior (Chantranupong et al, 2023;Krok et al, 2023).…”